Existing guidelines recommend colorectal cancer (CRC) screening for all patients over age 50. However, CRC remains the second leading cause of cancer death among Americans largely because colonoscopic screening of all the >100 million Americans over age 50 is unfeasible for both patient-related (non-compliance) and societal (inadequate endoscopic capacity and funding) reasons. Furthermore, the current practice of colonoscopy on the 3average risk4 population is remarkably inefficient2only ~6% of the screening population has significant neoplasia (advanced adenomas). Thus, a simple, non-invasive risk-stratification technique is critical to better target patients for colonoscopy. Stool analysis would be an ideal test that would engender the best patients6 compliance, although current stool tests assessing tumor cells or blood loss have dismal sensitivity. We propose a novel, more robust approach that utilizes mucus layer fecal colonocytes which are abraded from the epithelium and thus represent field carcinogenesis (the genetic/environmental fingerprint of neoplastic risk). Based on our preliminary data (156 patients), we hypothesize that the analysis of two complementary facets, nanostructural and molecular (microRNA) alterations, in mucus layer fecal colonocytes will serve as a highly accurate means of identifying field carcinogenesis and thereby serve as a non-invasive CRC screening test. Our approach is based on the combination of a novel biophotonics technology, partial wave spectroscopic microscopy (PWS), that is uniquely capable of imaging and quantification of the statistics of cell nanoscale organization and a new method to get high quality non-apoptotic fecal colonocytes in a practical fashion. In preclinical and clinical models, the performance characteristics of PWS and microRNA were outstanding, thus providing promise for a screening test. There are several requisite steps prior to the future definitive clinical validation. We will develop high-throughput PWS technology and identify the cellular location of the nanoarchitectural alterations. We will formulate and prospectively test a prediction rule that combines both nanostructural and molecular alterations. This project will confirm that nanostructural/ molecular stool analysis may provide sensitive, non-invasive risk-stratification tool, thereby heralding the era of personalized medicine for CRC population screening.